PT93576B - METHOD FOR PREPARING NEW PHENYLAMINOETHANOL DERIVATIVES WITH BRONCHOSPASMOLITIC ACTIVITY AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents
METHOD FOR PREPARING NEW PHENYLAMINOETHANOL DERIVATIVES WITH BRONCHOSPASMOLITIC ACTIVITY AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM Download PDFInfo
- Publication number
- PT93576B PT93576B PT93576A PT9357690A PT93576B PT 93576 B PT93576 B PT 93576B PT 93576 A PT93576 A PT 93576A PT 9357690 A PT9357690 A PT 9357690A PT 93576 B PT93576 B PT 93576B
- Authority
- PT
- Portugal
- Prior art keywords
- general formula
- compound
- compounds
- process according
- group
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
DESCRIÇÃODESCRIPTION
DAGIVES
PATENTE DE INVENÇÃOINVENTION PATENT
N.° 93.576No. 93,576
REQUERENTE: AKTIEBOLAGET DRACO, sueca, com sede emAPPLICANT: AKTIEBOLAGET DRACO, Swedish, established in
S-221 00 Lund, SuéciaS-221 00 Lund, Sweden
EPÍGRAFE: Processo para a preparação de novos derivados de fenilaminoetanol com actividade broncospasmolítica e de composições farmacêuticas que os contêmEPIGRAPH: Process for the preparation of new phenylaminoethanol derivatives with bronchospasmolytic activity and pharmaceutical compositions containing them
INVENTORES: Otto Agne Torsten Olsson,INVENTORS: Otto Agne Torsten Olsson,
Peter Juhan Pedaja,Peter Juhan Pedaja,
Leif Àke Svensson,Leif Àke Svensson,
Cari Bertil Waldeck,Carl Bertil Waldeck,
Kjell Ingvar Leopold Wetterlin,Kjell Ingvar Leopold Wetterlin,
Reivindicação do direito de prioridade ao aorigo do artigo 4° da Convenção de Paris de 20 de Março de 1883.Claim of the right of priority under Article 4 of the Paris Convention of 20 March 1883.
Suécia, 28 de Março de 1989, sob o No 8901060-7 inP' MCO :‘2 fl r 1*732Sweden, March 28, 1989, under No. 8901060-7 inP 'MCO: ‘2 fl r 1 * 732
AKTIEBOLAGET DRACOAKTIEBOLAGET DRACO
PROCESSO PARA A PREPARAÇÃO DE NOVOS DERIVADOS DE FENILAMINOETANOL COM ACTIVIDADE BRONCOSPASMOLlTICA E DE COMPOSIÇÕESPROCESS FOR THE PREPARATION OF NEW PHENYLAMINOETHANOL DERIVATIVES WITH BRONCOSPASMOLLIC ACTIVITY AND COMPOSITIONS
FARMACÊUTICAS QUE OS CONTÊMPHARMACEUTICALS THAT CONTAIN THEM
Campo da invençãoField of invention
A presente invenção refere-se a novos compostos com actividade terapêutica, aos processos para a sua preparação, a composições farmacêuticas que os contêm e ã utilização medicinal desses compostos. Em particular, os compostos da presente invenção têm um efeito espasmolítico sobre os brônquios e sao eficazes no tratamento de doenças dos pulmões obstrutivas reversíveis, de diversa etiologia, particularmente nas situações asmáticas. Os compostos, quando possuem uma configuração estereo química adequada, exibem uma duração de acção terapêutica prolon gada após inalação e reduzido grau de efeitos indesejáveis, especialmente efeito estimulador do coração reduzido.The present invention relates to novel compounds with therapeutic activity, to the processes for their preparation, to pharmaceutical compositions containing them and to the medicinal use of these compounds. In particular, the compounds of the present invention have a spasmolytic effect on the bronchi and are effective in the treatment of reversible obstructive lung diseases, of different etiology, particularly in asthmatic situations. The compounds, when they have an appropriate stereochemical configuration, exhibit a prolonged duration of therapeutic action after inhalation and a reduced degree of undesirable effects, especially reduced heart stimulating effect.
Antecedentes da invençãoBackground of the invention
É desejável descobrir agentes broncodilatadores com maior duração de acçao do que as substâncias presentemente comerciali-2zadas. Uma maior duração da acção tornará possível uma protecção adequada para os doentes asmáticos, quer durante a noite quer durante as primeiras horas da manhã em que a asma é usualmente pior. Os fármacos broncodilatadores utilizados correntemente para a terapêutica de inalação, por exemplo o fenoterol, o salbu tamol, a terbutalina e o bitolterol, têm, geralmente, uma duração de acção que dura apenas 4 a 6 horas e, portanto, não dão protecção adequada durante a noite se tomados no momento de deitar. 0 bitolterol está descrito por Kass, I. e Mingo. T.S.,It is desirable to discover bronchodilating agents with a longer duration of action than substances presently commercialized. A longer duration of action will make it possible to provide adequate protection for asthmatic patients, either at night or during the early hours of the morning when asthma is usually worse. Bronchodilator drugs currently used for inhalation therapy, for example fenoterol, salbu tamol, terbutaline and bitolterol, generally have a duration of action that lasts only 4 to 6 hours and therefore do not provide adequate protection during the night if taken at bedtime. Bitolterol is described by Kass, I. and Mingo. T.S.,
A new iongacting bronchodilator with reduced chronotopic effects in Chest, 78 (1980) 283. Compostos descritos na patente de invenção norte-americana NQ. 4 072 760 que são estreitamente aparentados sob o ponto de vista estrutural com os compostos do presente pedido de patente de invenção, mas apenas com acção de curta duração.A new iongacting bronchodilator with reduced chronotopic effects in Chest, 78 (1980) 283. Compounds described in U.S. patent NQ. 4,072,760 which are structurally related to the compounds of the present patent application, but only with a short duration of action.
Tentativas para obter compostos com acçao broncopasmolítica de longa duraçao são referidos na bibliografia como, por exemplo, o formoterol e o salmeterol. 0 problema foi, contudo, encontrar compostos com actividade broncospasmolítica tendo uma duração de acção com utilidade clínica de, pelo menos, 12 horas após a inalaçao de um aerossol da substância micronizada. É ainda desejável que estes compostos se liguem firmemente ao tecido pulmonar de forma a que apenas quantidades menores dos compostos activos penetrem na circulação geral. Nesse sentido, o risco de induzir efeitos indesejáveis sistémicos, como palpi-3-Attempts to obtain compounds with long-acting bronchopasmolytic action are referred to in the literature as, for example, formoterol and salmeterol. The problem, however, was to find compounds with bronchospasmolytic activity having a duration of action with clinical utility of at least 12 hours after the inhalation of an aerosol of the micronized substance. It is furthermore desirable that these compounds bind tightly to the lung tissue so that only minor amounts of the active compounds enter the general circulation. In this sense, the risk of inducing systemic undesirable effects, such as palpi-3-
tações e tremor, fica minimizadoand tremor, is minimized
Descrição da invençãoDescription of the invention
Descobriu-se que os novos compostos de fórmula geral R3New compounds of the general formula R 3 were found
ΗΩ ?ΗΩ?
na qual e ^2’ ^S1-13^3 ou diferentes, representam, cada um, um átomo de hidrogénio ou de halognéneo ou um grupo hidroxi, OCHg ou OC2H5 ou e R2, considerados conjuntamente, formam uma cadeia -O-Cl^-O- ou -OCF2-O-;in which e ^ 2 '^ S 1 - 13 ^ 3 or different, each represent a hydrogen or halogen atom or a hydroxy group, OCHg or OC2H5 or and R 2 , taken together, form an -O- chain Cl2 -O- or -OCF 2 -O-;
representa um átomo de hidrogénio ou um grupo CH^;represents a hydrogen atom or a CH2 group;
representa um átomo de hidrogénio ou um grupo de fórmula geral -CO-Ry na qual R? representa um grupo alquilo de cadeia linear ou ramificada com a 16 átomos de carbono, arilo, -NHCHg ou -N(CH3)2;represents a hydrogen atom or a group of the general formula -CO-Ry in which R? represents a straight or branched chain alkyl group having 16 carbon atoms, aryl, -NHCHg or -N (CH 3 ) 2 ;
Rg representa um átomo de hidrogénio ou de halogéneo ou um grupo hidroxi, OCH^ ou OC^H^;Rg represents a hydrogen or halogen atom or a hydroxy group, OCH4 or OC4 H4;
e os seus sais aceitáveis sob o ponto de vista farmacêutico são muito eficazes e possuem longa duração de acção broncospasmolítica, especialmente quando administrados localmente nos pulmões, por exemplo após inalaçao de uma composição em nebulisador ou em aerossol desses compostos.and their pharmaceutically acceptable salts are very effective and have a long duration of bronchospasmolytic action, especially when administered locally in the lungs, for example after inhalation of a nebulizer or aerosol composition of these compounds.
Nos compostos de fórmula geral X citada antes, um grupo arilo refere-se a grupos arilo com 3 a 8 átomos de carbono, de preferência com 6, e halogéneo refere-se a flúor, cloro ou bromo. Sais aceitáveis sob o ponto de vista farmacêutico, da presente invenção, sao em especial os sais de adição de ácido. Podem, de um modo conveniente, preparar-se fazendo-se reagir os compostos que sao capazes de formar esses sais com um ácido orgânico ou inorgânico fisiologicamente compatível. Exemplos de ácidos orgânicos apropriados são o ácido acético, o ácido fumárico, o ácido tartárico, o ácido cítrico, o ácido maleico, o ácido succínico e o ácido benzóico. Exemplos de ácidos inorgânicos apropriados sao o ácido clorídrico, o ácido bromídrico, o ácido sulfúrico e o ácido fosfórico.In the compounds of formula X mentioned above, an aryl group refers to aryl groups having 3 to 8 carbon atoms, preferably 6, and halogen refers to fluorine, chlorine or bromine. Pharmaceutically acceptable salts of the present invention are, in particular, acid addition salts. They can conveniently be prepared by reacting compounds which are capable of forming such salts with a physiologically compatible organic or inorganic acid. Examples of suitable organic acids are acetic acid, fumaric acid, tartaric acid, citric acid, maleic acid, succinic acid and benzoic acid. Examples of suitable inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.
-5' χ-5 'χ
Os compostos da presente invenção exibem ainda um menor grau de efeitos indesejáveis cardiovasculares. A actividade farmacológica e a duração de acção dos novos compostos depende grandemente da sua configuração estereoquímica no átomo de carbono benzílico estereogénico, na cadeia de feniletanolamina e no átomo de carbono estereogénico do substituinte no átomo de azoto. Assim, o efeito farmacológico óptimo obtém-se apenas com a configuração R na posição benzílica e a duração é óptima com a configuração S no grupo substituinte no átomo de azoto. Compostos preferidos de acordo com a presente invenção são aqueles em que e R formam uma cadeia -OCI^-O- ou -OCF2-OR^ representa um átomo de hidrogénio ou um grupo metilo, R^ representa um átomo de hidrogénio e Rg representa um grupo metoxi.The compounds of the present invention further exhibit a lesser degree of cardiovascular undesirable effects. The pharmacological activity and duration of action of the new compounds depends largely on their stereochemical configuration on the stereogenic benzyl carbon atom, on the phenylethanolamine chain and on the stereogenic carbon atom of the substituent on the nitrogen atom. Thus, the optimal pharmacological effect is obtained only with the R configuration in the benzyl position and the duration is optimal with the S configuration in the substituent group on the nitrogen atom. Preferred compounds according to the present invention are those in which and R forms a chain -OCI ^ -O- or -OCF2-OR ^ represents a hydrogen atom or a methyl group, R ^ represents a hydrogen atom and Rg represents a methoxy group.
São especialmente preferidos os compostos de acordo com a presente invenção seguintes : o racémico (isómeros R,S + S,R) e o racémico (isómeros R,R + S,S) de 1-[(4-hidroxi)-3-(£-metoxibenzilamino)-fenil)]-2-[(l-metil-2-(3,4-metilenodioxifenil)-etil)-amino]-etanol.The following compounds according to the present invention are especially preferred: the racemic (R, S + S, R isomers) and the racemic (R, R + S, S isomers) of 1 - [(4-hydroxy) -3- (£ -methoxybenzylamino) -phenyl)] - 2 - [(1-methyl-2- (3,4-methylenedioxyphenyl) -ethyl) -amino] -ethanol.
Mais especialmente preferido, de acordo com a presente invenção, é o isómero 1-(R) - (4-hidroxi)-3-(jq-metoxibenzilamino) -fenil-2-[(1-(S)-metil-2-(3,4-metilenodioxifenil)-etil)-amino]-etanol.Most especially preferred, according to the present invention, is the isomer 1- (R) - (4-hydroxy) -3- (jq-methoxybenzylamino) -phenyl-2 - [(1- (S) -methyl-2- (3,4-methylenedioxyphenyl) -ethyl) -amino] -ethanol.
-6Preparagao-6Preparation
Os compostos de fórmula geral X preparam-se fazendo reagir 4-benziloxi-3-nitro-estirenoóxido de fórmulaThe compounds of general formula X are prepared by reacting 4-benzyloxy-3-nitro-styrene oxide of formula
(V) com um composto de fórmula geral(V) with a compound of general formula
na qual , R2 e R^ têm os significados definidos antes e representa um átomo de hidrogénio ou um grupo de fórmulain which R2 and R ^ have the meanings defined above and represent a hydrogen atom or a group of formula
CH3 CH 3
para se obter um composto de fórmula geralto obtain a compound of general formula
na qual depois do que através de umin which after than through a
Rg e têm os significados definidos antes, se hidrogena o composto VII para dar directamente composto de fórmula geralRg and have the meanings defined before, compound VII is hydrogenated to give directly compound of general formula
(VIII)(VIII)
na qualin which
R^, ^2 θ Rg têm o significado definido antes, depois do que se faz reagir o composto de fórmula geral IX com um composto de fórmula geralR ^, ^ 2 θ Rg have the meaning defined before, after which the compound of general formula IX is reacted with a compound of general formula
CHO na qualCHO in which
Rg tem o significado definido antes, conjuntamente com óxido de platina ou paládio sobre carvão e hidrogénio para se obter um composto de fórmula geral X na qual R^ representa um átomo de hidrogénio e Rp R^, Rg e Rg têm os significados definidos antes, sob a forma isomérica pura ou sob a forma de uma mistura de várias quantidades dos estereoisómeros possíveis, como se descreve a seguir.Rg has the meaning defined above, together with platinum or palladium oxide on carbon and hydrogen to obtain a compound of general formula X in which R ^ represents a hydrogen atom and Rp R ^, Rg and Rg have the meanings defined above, in pure isomeric form or as a mixture of various amounts of the possible stereoisomers, as described below.
-9V •*7?-9V • * 7?
Método geral de preparaçãoGeneral method of preparation
H-N [XH-N [X
(R5 = Η)(R 5 = Η)
Método AMethod A
Este método é utilizado para a preparaçao de estereoisómeros e eplmeros puros que diferem apenas na configuração na posição benzílica. (R^, θ Rg têm o significado definido antes).This method is used for the preparation of pure stereoisomers and eplers that differ only in the configuration in the benzyl position. (R ^, θ Rg have the meaning defined before).
RR
Diastereómeros separados por recristalização ou cromatografiaDiastereomers separated by recrystallization or chromatography
Diastereómeros separados também por cromatografiaDiastereomers also separated by chromatography
Método BMethod B
Este método é utilizado para a preparação de racematos e de misturas de racematos. (Rp R2, Rg e Rg têm o significado definido antes),This method is used for the preparation of racemates and mixtures of racemates. (Rp R 2 , Rg and Rg have the meaning defined before),
Preparaçao de compostos iniciaisPreparation of starting compounds
Aminas VIAmines VI
Método CMethod C
Preparação de enanteómeros purosPreparation of pure enantiomers
Faz-se reagir 1-fenil-2-propanonas substituídas apropriadas com R- ou S-metil-benzilamina seguindo-se a redução da imina por níquel de Raney obtendo-se a R,R-amina ou S,S-amina pura, respectivamente.The appropriate substituted 1-phenyl-2-propanones are reacted with R- or S-methyl-benzylamine followed by reduction of the imine by Raney nickel to obtain R, R-amine or S, pure S-amine, respectively.
Rl e &2 te™ ° significado definido antes.Rl e & 2 te ™ ° meaning defined before.
isómero R,R ou S,SR, R or S, S isomer
-15Método D-15 Method D
Preparação de aminas racémicas VIPreparation of racemic amines VI
Faz-se reagir benzaldeído apropriadamente substituídos com um nitroalcano seguindo-se a redução para se obter a amina.Benzaldehyde is reacted appropriately substituted with a nitroalkane followed by reduction to obtain the amine.
R-p R£ e R3 têm o significado definido antes.Rp R £ and R3 have the meaning defined before.
EpóxidoEpoxide
Prepara-se o óxido de 4-benziloxi-3-nitroestireno, racémico pelo método descrito por Kaisco et al·., J. Med. Chem. 17 (1974) 49.Racemic 4-benzyloxy-3-nitrostyrene oxide is prepared by the method described by Kaisco et al., J. Med. Chem. 17 (1974) 49.
EXEMPLOSEXAMPLES
Exemplo 1 (Preparação de acordo com o método A)Example 1 (Preparation according to method A)
1- (R) - (4-hidroxi) - 3- (-metoxibenzilamino) -fen.il-2- [ (1- (S) -metil-2-(3,4-metil·enodioxifenil)-etil)-amino]-etanol (X)1- (R) - (4-hydroxy) - 3- (-methoxybenzylamino) -phenyl-2- [(1- (S) -methyl-2- (3,4-methyl · enodioxiphenyl) -ethyl) - amino] -ethanol (X)
1-(4-benziloxi-3-nitrofenil)-2-(N-metilbenzil-l-metil-2-(3,4-metilenodioxifenil)-etilamino-etanol (VII) (isómeros R,S,S e S , S , S) .1- (4-benzyloxy-3-nitrophenyl) -2- (N-methylbenzyl-1-methyl-2- (3,4-methylenedioxyphenyl) -ethylamino-ethanol (VII) (R, S, S and S, S isomers , S) .
Agitaram-se 23,9 g (88 mmoles) de 4-benziloxi-3-nitro-estirenóxido (V) e 24,9 g (88 mmoles) de (S,S)-N-l-fenetil-1-(1,3-benzodioxol-5-il)-2-propanamina (VI), à temperatura de 150°C sob atmosfera de azoto durante 15 horas. Dissolveu-se o produto impuro em acetato de etilo, adicionou-se ácido clorídrico concentrado e evaporou-se o dissolvente para se obter o cloridrato impuro sob uma forma sólida. A recristalização em acetato de etilo deu 17,3 g de isómeros S,S,S e R,S,S a 85/15. A concentração do líquido-mae deu 29 g dos isómeros impuros R,S,S e23.9 g (88 mmoles) of 4-benzyloxy-3-nitro-styreneoxide (V) and 24.9 g (88 mmoles) of (S, S) -N1-phenethyl-1- (1.3) were stirred -benzodioxol-5-yl) -2-propanamine (VI), at 150 ° C under a nitrogen atmosphere for 15 hours. The crude product was dissolved in ethyl acetate, concentrated hydrochloric acid was added and the solvent was evaporated to obtain the crude hydrochloride in a solid form. Recrystallization from ethyl acetate gave 17.3 g of 85/15 S, S, S and R, S, S isomers. The concentration of the mother liquor gave 29 g of the impure isomers R, S, S and
S,S,S a 70/30. A cromatografia rápida do líquido-mãe concentradoS, S, S at 70/30. Flash chromatography of the concentrated mother liquor
-18/ (éster do petróleo/acetato de etilo a 2,5/1, sílica) deu 21,3 g de uma mistura de isõmeros a 70/30. Os isõmeros puros R,S,S e-18 / (petroleum ester / 2.5 / 1 ethyl acetate, silica) gave 21.3 g of a 70/30 mixture of isomers. The pure isomers R, S, S and
S,S,S obtiveram-se, respectivamente, por cromatografia rápida repetida e por cromatografia com cianeto de metilo/sílica.S, S, S were obtained, respectively, by repeated flash chromatography and by chromatography with methyl cyanide / silica.
Prepararam-se os isomeros R,R,R e S,R,R, identicamente.The R, R, R and S, R, R isomers were prepared identically.
1-(4-benziloxi-3-aminofenil)-2-(N-metilbenzil-l-metil-2(3,4-metilenodioxifenil)-etilamino-etanol (VII) (isõmeros R,S,S e S , S , S) .1- (4-benzyloxy-3-aminophenyl) -2- (N-methylbenzyl-1-methyl-2 (3,4-methylenedioxyphenyl) -ethylamino-ethanol (VII) (R, S, S and S, S, S isomers, S) .
Dissolveram-se 10,8 g (20 mmoles) do correspondente composto nitro (R,S,S/S,S,S na relação 70/30) em 250 ml de metanol. Adicionaram-se 23 g (100 mmoles) de SnC^^l^O e aqueceu-se a solução ã temperatura de 60°C. Durante 50 minutos adicionaram-se por porções 400 g de boro-hidreto de sódio. Após agitaçao durante mais 40 minutos à temperatura de 60°C, concen-19trou-se a solução para 150 ml e, em seguida, adicionaram-se 350 ml de solução de hidróxido de sódio 0,5 N seguidos de 200 ml de éter dietílico. A extracção da fase aquosa com mais éter dietílico, secagem e evaporação, deu 7,9 g de um produto oleoso. A cromatografia, (cianeto de metilo/sílica) deu 4,5 g do isómero R,S,S puro e 1,5 g do isómero S,S,S.10.8 g (20 mmoles) of the corresponding nitro compound (R, S, S / S, S, S in the ratio 70/30) were dissolved in 250 ml of methanol. 23 g (100 mmoles) of SnC ^^ l l ^O were added and the solution was heated to 60 ° C. For 50 minutes, 400 g of sodium borohydride was added in portions. After stirring for a further 40 minutes at 60 ° C, the solution was concentrated to 150 ml and then 350 ml of 0.5 N sodium hydroxide solution was added followed by 200 ml of diethyl ether . Extraction of the aqueous phase with more diethyl ether, drying and evaporation, gave 7.9 g of an oily product. Chromatography (methyl cyanide / silica) gave 4.5 g of the pure R, S, S isomer and 1.5 g of the S, S, S isomer.
RMN (isómero R,S,S, CDCl^);NMR (R, S, S, CDCl3 isomer);
7,46-6,33 (m, 16H); 5,87 (d, 2H); 5,09 (s, 2H); 7.46-6.33 (m, 16H); 5.87 (d, 2H); 5.09 (s, 2H) ;
4,54 (dd, ÍH); 4,08 (q, ÍH); 3,05-2,02 (m, 5H);4.54 (dd, 1H); 4.08 (q, 1H); 3.05-2.02 (m, 5H);
1,50 (d, 3H); 0,97 (d, 3H).1.50 (d, 3H); 0.97 (d, 3H).
(isómero S,S,S);(S, S, S isomer);
7,43-6,25 (m, 16H); 5,85 (d, 2H); 5,05 (s, 2H);7.43-6.25 (m, 16H); 5.85 (d, 2H); 5.05 (s, 2H);
4,38 (dd, ÍH); 4,08 (q, ÍH); 3,11 (m, ÍH); 2,81-2,36 (m, 4H); 1,41 (d, 3H); 0,95 (d, 3H).4.38 (dd, 1H); 4.08 (q, 1H); 3.11 (m, 1H); 2.81 - 2.36 (m, 4H) ; 1.41 (d, 3H); 0.95 (d, 3H).
Preparou-se o monocloridrato do isómero R,S,S fazendo-se reagir 0,58 ml de cloreto de acetilo com 180 ml de metanol seguido da adiçao de 4,5 g da base e de evaporaçao. Após lavagem com éter dietílico, obtiveram-se 4,3 g de monocloridrato sob a forma de um sal. Prepararam-se, do mesmo modo, os isõmeros S,R,R e R, R, R.The R, S, S isomer monohydrochloride was prepared by reacting 0.58 ml of acetyl chloride with 180 ml of methanol followed by the addition of 4.5 g of the base and evaporation. After washing with diethyl ether, 4.3 g of monohydrochloride were obtained as a salt. The S, R, R and R, R, R isomers were prepared in the same way.
(R)-1-(3-amino-4-hidroxifenil)-2-[(S)-1-meti1-2-(3,4-metilenodioxifenil)-etilamino]-etanol (IX)(R) -1- (3-amino-4-hydroxyphenyl) -2 - [(S) -1-methyl1-2- (3,4-methylenedioxyphenyl) -ethylamino] -ethanol (IX)
Dissolveram-se 4,3 g (8 mmoles) do composto anterior (isómero R,S,S) sob a forma de cloridrato, em 75 ml de metanol e adicionou-se 0,3 g de paládio sobre carvao a 10Z e hidrogenou-se a mistura numa atmosfera de 40 psi durante 5 horas. Filtrou-se a solução metanólica e utilizou-se'esta solução na fase, seguinte. Prepararam-se os isómeros S,S,S, R,R,R e S,R,R de IX de um modo t4.3 g (8 mmoles) of the previous compound (R, S, S isomer) was dissolved in the form of hydrochloride in 75 ml of methanol and 0.3 g of palladium on coal at 10Z was added and hydrogenated. the mixture in an atmosphere of 40 psi for 5 hours. The methanolic solution was filtered and this solution was used in the next phase. IX, S, S, S, R, R, R and S, R, R isomers were prepared in a t
similar. >similar. >
1(R) - (4-hidroxi) -3- (jj-metoxibenzilamino) -fenil-2- [ (1- (S) -metil-2-(3,4-metilenodioxifenil)-etil)-amino]-etanol (X)1 (R) - (4-hydroxy) -3- (j-methoxybenzylamino) -phenyl-2- [(1- (S) -methyl-2- (3,4-methylenedioxyphenyl) -ethyl) -amino] -ethanol (X)
Adicionaram-se 2 ml (16 mmoles) de p-anisaldeído à solução metanólica obtida anteriormente do isómero R,S,S de IX. Após refluxo durante 30 minutos adicionaram-se 30 mg de óxido de platina e hidrogenou-se a mistura a 50 psi durante 1 hora e 30 minutos. Obteve-se 2,3 g do produto impuro (pureza de 90Z). A cromatografia com clorofórmio/sílica da base e adição de ácido sulfúrico/etanol deu 1,2 g de IV puro, sob a forma do seu sulfato2 ml (16 mmoles) of p-anisaldehyde was added to the methanolic solution obtained previously from the R, S, S isomer of IX. After reflux for 30 minutes, 30 mg of platinum oxide was added and the mixture was hydrogenated at 50 psi for 1 hour and 30 minutes. 2.3 g of the crude product (90 Z purity) were obtained. Chromatography with chloroform / silica of the base and addition of sulfuric acid / ethanol gave 1.2 g of pure IV, as its sulfate
RMN (isómero R,S, DMSO);NMR (R, S, DMSO isomer);
7,3-6,40 (m, 10H); 5,99 (s, 2H); 4,52 (d, 1H);7.3-6.40 (m, 10H); 5.99 (s, 2H); 4.52 (d, 1H);
4,23 (s, 2H); 3,71 (s, 3H); 3,08 (s largo, 1H); 2,89-2,44 (m e DMSO); 0,99 (d, 3H).4.23 (s, 2H); 3.71 (s, 3H); 3.08 (broad s, 1H); 2.89-2.44 (m and DMSO); 0.99 (d, 3H).
De um modo semelhante prepararam-se os isómeros S,S S,R e R,R de X.In a similar way, the S, S S, R and R, R isomers of X were prepared.
RMN (isómero S,S);NMR (S, S isomer);
7,31-6,42 (m, 10H); 5,98 (s, 2H); 4,53 (m, 1H);7.31-6.42 (m, 10H); 5.98 (s, 2H); 4.53 (m, 1H);
4,26 (s, 2H); 3,74 (s, 3H); 3,1 (m, 1H); 2,90-2,45 (m, e DMSO); 1,02 (d, 3H).4.26 (s, 2H); 3.74 (s, 3H); 3.1 (m, 1H); 2.90-2.45 (m, and DMSO); 1.02 (d, 3H).
Exemplo 2 (Preparação de acordo com o método B)Example 2 (Preparation according to method B)
Preparação dos racematos (isómeros R,S+S,R) de 1-(4-hidroxi) -3- (js-metoxibenzilamino) -fenil-2- [ (l-metil-2- (3,4-metilenodioxifenil)-etil)-amino]-etanol.Preparation of the racemates (R, S + S, R isomers of 1- (4-hydroxy) -3- (js-methoxybenzylamino) -phenyl-2- [(1-methyl-2- (3,4-methylenedioxyphenyl) - ethyl) -amino] -ethanol.
1-(4-benziloxi-3-nitrofenil-2-((l-metil-2-(3,4-metilenodioxifenil) ) -etil) -amino-etanol VII (misturas diversas dos isómeros R,R R,S e S,R)1- (4-benzyloxy-3-nitrophenyl-2 - ((1-methyl-2- (3,4-methylenedioxyphenyl)) -ethyl) -amino-ethanol VII (different mixtures of the R, RR, S and S isomers, R)
Submeteu-se a refluxo 1,4 g (5 mmoles) de óxido de (R/S)-4-benziloxi-3-nitroestireno e 1,1 g (6 mmoles) de (R/S)-1-(3,4)-metilenodioxifenil)-2-aminopropano (VI) em 10 ml de metanol durante 20 horas. Após a evaporação do metanol, a mistura isomérica dissolveu-se em éter dietílico e cristalizaram-se os isómeros R,S e S,R obtendo-se 0,4 g do racemato. (Os isómeros R,R e S,S foram removidos).Reflux 1.4 g (5 mmoles) of (R / S) -4-benzyloxy-3-nitrostyrene oxide and 1.1 g (6 mmoles) of (R / S) -1- (3, 4) -methylenedioxyphenyl) -2-aminopropane (VI) in 10 ml of methanol for 20 hours. After evaporation of methanol, the isomeric mixture was dissolved in diethyl ether and the R, S and S, R isomers were crystallized to obtain 0.4 g of the racemate. (The R, R and S, S isomers have been removed).
RMN (CDClg);NMR (CDClg);
7,8 (d, 1H); 7,5-6,5 (m, 10H) ; 5,9 (s, 2H); 5,2 (s, 2H); 4,6 (dd, 1H); 3,0-2,5 (m, 5H); 1,2 (d, 3H).7.8 (d, 1H) ; 7.5-6.5 (m, 10H); 5.9 (s, 2H); 5.2 (s, 2H); 4.6 (dd, 1H); 3.0-2.5 (m, 5H); 1.2 (d, 3H).
«Ο«Ο
Hidrogenou-se ο racemato com paládio sobre carvão em etanol para se obter o aminofenol correspondente (IX). Em seguida, fez-se reagir com £-anisaldeído, como descrito anteriormente, obtendo-se o racémico (isómeros R,S + S,R) do composto X descrito anteriormente. A mistura isomérica R,R + S,S preparou-se a partir da mistura isomérica removida previamente, deThe racemate was hydrogenated with palladium on charcoal in ethanol to obtain the corresponding aminophenol (IX). Then, it was reacted with β-anisaldehyde, as previously described, obtaining the racemic (R, S + S, R isomers) of compound X described above. The isomeric mixture R, R + S, S was prepared from the isomeric mixture previously removed,
VII.VII.
Processo geral para a preparação de compostos de fórmula geral X cloridrato do composto nitro correspondente VII dissolveu-se em etanol. Adicionou-se paládio sobre carvao a 10Z e submeteu-se a hidrogenação à temperatura ambiente durante 4 a 20 2 horas, apressao de 3,5 kg/cm (50 psi). Separou-se o catalisador por filtração e adicionou-se benzaldeído ou £-metoxibenzaldeído.General process for the preparation of compounds of the general formula X hydrochloride of the corresponding nitro compound VII was dissolved in ethanol. Palladium on coal at 10Z was added and subjected to hydrogenation at room temperature for 4 to 20 hours, at a pressure of 3.5 kg / cm (50 psi). The catalyst was filtered off and benzaldehyde or β-methoxybenzaldehyde was added.
Após refluxo durante 1 hora adicionou-se óxido de platina e hidrogenou-se à pressão de 1 atmosfera durante cerca de 24 horas 2 ou 3,5 kg/cm (50 psi) durante 45 minutos. Lavou-se o cloridrato não purificado com éter dietilico, retomou-se a base com acetato de etilo e purificou-se por cromatografia em coluna de gel de sílica utilizando uma mistura de clorofórmio/metanol como eluente (10/2). A base não purificada foi transformada em seguida no cloridrato ou no sulfato.After reflux for 1 hour, platinum oxide was added and hydrogenated at 1 atmosphere pressure for about 24 hours 2 or 3.5 kg / cm (50 psi) for 45 minutes. The unpurified hydrochloride was washed with diethyl ether, the base was taken up with ethyl acetate and purified by column chromatography on silica gel using a chloroform / methanol mixture as eluent (10/2). The unpurified base was then converted to hydrochloride or sulfate.
-23Exemplo 3-23Example 3
1-(4-hidroxi-3-benzilamino-fenil-2-(l-metil-2-(3,4-metilenodioxifenil)-etilamino)-etanol (X) (Mistura R,S+S,R+R,R+S,S)1- (4-hydroxy-3-benzylamino-phenyl-2- (1-methyl-2- (3,4-methylenedioxyphenyl) -ethylamino) -ethanol (X) (Mixture R, S + S, R + R, R + S, S)
A partir de 2,4 g do composto VII, 0,7 g de paládio sobre carvão, 1,1 g de benzaldeído e 40 mg de óxido de platina obteve-se 1,2 g do cloridrato.From 2.4 g of compound VII, 0.7 g of palladium on charcoal, 1.1 g of benzaldehyde and 40 mg of platinum oxide, 1.2 g of the hydrochloride were obtained.
RMN: (DMSO-Dg como dissolvente e referência) d; 7,4-6,4 (m, 11H); 6,01 (s, 2H); 5,90 (d, ÍH);NMR: (DMSO-Dg as solvent and reference) d; 7.4-6.4 (m, 11H); 6.01 (s, 2H); 5.90 (d, 1H);
5,35 (s largo, ÍH); 4,72 (m, ÍH); 4,35 (s, 2H);5.35 (broad s, H); 4.72 (m, 1H); 4.35 (s, 2H);
3,37 (s, 3H); 3,1-2,9 (m, 4H); 1,10 (d, 3H).3.37 (s, 3H); 3.1-2.9 (m, 4H); 1.10 (d, 3H).
Exemplo 4Example 4
1-(4-hidroxi-3-p-metoxibenzilamino-feni1)-2-(l-metil-2-(3,4-dimetoxifenil)-etilamino)-etanol (X) (Mistura R,S+S,S)1- (4-hydroxy-3-p-methoxybenzylamino-phenyl) -2- (1-methyl-2- (3,4-dimethoxyphenyl) -ethylamino) -ethanol (X) (Mixture R, S + S, S)
A partir de 5,2 g do composto nitro VII, 0,5 g de Pd/C,From 5.2 g of nitro VII compound, 0.5 g of Pd / C,
3,0 g de £-metoxibenzaldeído e 50 mg de PtC^, obteve-se 1,0 g do cloridrato.3.0 g of β-methoxybenzaldehyde and 50 mg of PtC4, 1.0 g of the hydrochloride was obtained.
RMN: (como anteriormente) d; 7,28 (d, 2H, 7,0-6,5 (m, 8H); 4,6 (m, ÍH); 4,22 (2H); 3,74 (9H);NMR: (as before) d; 7.28 (d, 2H, 7.0-6.5 (m, 8H); 4.6 (m, 1H); 4.22 (2H); 3.74 (9H);
3,7-2,8 (m); 1,2 (d, 3H).3.7-2.8 (m); 1.2 (d, 3H).
-24Exemplo 5-24Example 5
1-(4-hidroxi-3-p-metoxibenzilamino-fenil)-2-(1,1-dimetil-2-(3,4-metilenodioxifenil)-etilamino)-etanol (X) (Racemato R/S)1- (4-hydroxy-3-p-methoxybenzylamino-phenyl) -2- (1,1-dimethyl-2- (3,4-methylenedioxyphenyl) -ethylamino) -ethanol (X) (Racemate R / S)
A partir de 5,0 g do composto nitro VII, 0,3 g de Pd/C,From 5.0 g of nitro VII compound, 0.3 g of Pd / C,
4,9 ml de p-metoxibenzaldeído e 30 mg de óxido de platina, obtiveram-se 3,1 g do produto sob a forma de cloridrato.4.9 ml of p-methoxybenzaldehyde and 30 mg of platinum oxide, 3.1 g of the product were obtained in the form of hydrochloride.
RMN: (como anteriormente) d; 7,3 (d, 2H); 6,9-6,4 (m, 8H) ·, 6,0 (s, 2H) ; 5,93 (m, 1H) ; 5,24 (s largo, 1H); 4,73 (d largo, 1H); 4,25 (s, 2H); 3,70 (s, 3H); 3,37 (s, 2H); 2,89 (m, largo e s, 5H); 1,19 (s, 3H).NMR: (as before) d; 7.3 (d, 2H); 6.9-6.4 (m, 8H) ·, 6.0 (s, 2H); 5.93 (m, 1H); 5.24 (broad s, 1H) ; 4.73 (broad d, 1H); 4.25 (s, 2H); 3.70 (s, 3H); 3.37 (s, 2H); 2.89 (m, wide, 5H); 1.19 (s, 3H).
Exemplo 6Example 6
1-(4-hidroxi-3-p-metoxibenzilamino-fenil)-2-(l-metil-2-(p-metoxifenil)-etilamino)-etanol (X) (Mistura R,S+S,S)1- (4-hydroxy-3-p-methoxybenzylamino-phenyl) -2- (1-methyl-2- (p-methoxyphenyl) -ethylamino) -ethanol (X) (Mixture R, S + S, S)
A partir de 7,7 g do composto nitro VII, 0,3 g de paládio sobre carvao, 6,5 g de £-metoxibenzaldeído e 30 mg de óxido de platina, obtiveram-se 0,6 g do produto sob a forma de sulfato.From 7.7 g of nitro compound VII, 0.3 g of palladium on coal, 6.5 g of β-methoxybenzaldehyde and 30 mg of platinum oxide, 0.6 g of the product were obtained in the form of sulfate.
RMN: (como anteriormente) d; 7,28 (d, 2H); 7,14-6,36 (m, 11H); 5,12 (s largo, 1H); 4,52 (m, 1H); 4,22 (s, 2H); 3,72 (2d, 6H); 3,4-2,5 (m, incl. DMSO);NMR: (as before) d; 7.28 (d, 2H); 7.14-6.36 (m, 11H); 5.12 (broad s, 1H); 4.52 (m, 1H); 4.22 (s, 2H); 3.72 (2d, 6H); 3.4-2.5 (m, incl. DMSO);
1,0 (d, 3H).1.0 (d, 3H).
-25Exemplo 7-25Example 7
1-(4-hidroxi-3-p-metoxibenzilamino-fenil)-2-(l-metil-2-fenil-etilamino)-etanol (X)1- (4-hydroxy-3-p-methoxybenzylamino-phenyl) -2- (1-methyl-2-phenyl-ethylamino) -ethanol (X)
A partir de 2,5 g do composto nitro VII, obtiveram-se 260 mg do produto sob a forma de sulfato.From 2.5 g of the nitro VII compound, 260 mg of the product were obtained in the form of sulphate.
RMN: (como anteriormente) d; 7,4-6,4 (m, 12H); 5,15 (s, ÍH); 4,59 (s largo, ÍH); 4,22 (s, 2H); 3,70 (s, 3H) ·, 3,2-2,5 (m, incl DMSO) ; 1,0 (dd, 3H),.NMR: (as before) d; 7.4-6.4 (m, 12H); 5.15 (s, 1H); 4.59 (broad s, H); 4.22 (s, 2H); 3.70 (s, 3H) ·, 3.2-2.5 (m, incl DMSO); 1.0 (dd, 3H).
tí.you.
ctíctí
O ♦r-l εO ♦ r-l ε
o cr othe cr the
<u μ<u μ
<u<u
4-14-1
CO wCO w
co·, oá :co ·, oá:
ΙΖΊΙΖΊ
Pá en-, pá_<Shovel en-, shovel_ <
PáPan
PáPan
cncn
X oX o
o x ι ι Xo x ι ι X
I I I I I I I II I I I I I I I
ι ι ι ι ι ι ι ι ι Xι ι ι ι ι ι ι ι ι X
C4 en <rC4 en <r
UO ΌOu Ό
Γ-27Compostos iniciais de fórmula geral (VI)Γ-27Initial compounds of general formula (VI)
CH(CH-)PhCH (CH-) Ph
Nos exemplos específicos seguintes sao descritas as preparações dos compostos indicados no Quadro 2:The following specific examples describe the preparations of the compounds listed in Table 2:
Composto S8Compound S8
N-l-(S)-fenetil-l-fenil-2-(S)-propanaminaN-l- (S) -phenethyl-l-phenyl-2- (S) -propanamine
Submeteram-se a refluxo 13,4 g (0,1 mole) de fenilacetona e 10,9 g de (S)-fenetilamina em 200 ml de benzeno num aparelho13.4 g (0.1 mole) of phenylacetone and 10.9 g of (S) -phenethylamine in 200 ml of benzene were refluxed in an apparatus
Dean-Stark durante 3 horas. Após evaporação do dissolvente, dissolveu-se o resíduo em etanol, adicionou-se Níquel de Raney e 2 realizou-se a hidrogenaçao durante a noite a 3,5 kg/cm (50 psi). Purificou-se o produto por recristalizaçao do cloridrato em acetona e etanol. Rendimento 8,1 g, sob a forma de base.Dean-Stark for 3 hours. After evaporation of the solvent, the residue was dissolved in ethanol, Raney Nickel was added and hydrogenation was carried out overnight at 3.5 kg / cm (50 psi). The product was purified by recrystallizing the hydrochloride from acetone and ethanol. Yield 8.1 g, as a base.
RMN: (CDC13, TMS como ref.) d; 7,33-7,06 (m, 10H) ,NMR: (CDCl 3 , TMS as ref.) D; 7.33-7.06 (m, 10H),
3,92 (1, 1H); 2,87 (dd, 1H); 2,75 (sexteto, 1H);3.92 (1.1H); 2.87 (dd, 1H); 2.75 (sextet, 1H);
2,48 (dd, 1H); 1,29 (d, 3H); 0,90 (d, 3H).2.48 (dd, 1H); 1.29 (d, 3H); 0.90 (d, 3H).
Composto S3Compound S3
N-l-(S)-fenetil-1-(4-metoxifenii)-2-(S)-propanaminaN-l- (S) -phenethyl-1- (4-methoxyphenyl) -2- (S) -propanamine
Preparou-se como indicado anteriormente a partir de 16,4 g de cetona e 10,9 g de (S)-1-fenetilamina obtendo-se 12,5 g do produto após cromatografia em coluna de gel de sílica (clorofórmio/metanol, 10/2).It was prepared as previously indicated from 16.4 g of ketone and 10.9 g of (S) -1-phenethylamine obtaining 12.5 g of the product after chromatography on a column of silica gel (chloroform / methanol, 10/2).
-29*r-29 * r
Composto SISI compound
N-l-(S)-fenetil-1-(1, 3-benzodioxol-4-il)-2-(S)-propanamida e o isómero R,R correspondente, prepararam-se de um modo análogo a partir de (1,3-metilenodioxi)-fenil-acetona.N1- (S) -phenethyl-1- (1,3-benzodioxol-4-yl) -2- (S) -propanamide and the corresponding R, R isomer, were prepared in an analogous manner from (1, 3-methylenedioxy) -phenyl-acetone.
Composto S5Compound S5
1-(3,4-metilenodioxifenil)-2-metil-2-(R/S)-aminopropano1- (3,4-methylenedioxyphenyl) -2-methyl-2- (R / S) -aminopropane
Adicionou-se uma solução de 360 g (2,4 moles) de piperonal em 684 g (7,7 mole) de 2-nitropropano a 2,4 moles de metóxido de sódio em 360 ml de metanol recentemente preparado, à temperatura de 15°C. Após agitação ã temperatura ambiente durante a noite adicionaram-se 480 ml de ácido sulfúrico 5N. Em seguida, verteu-se a mistura reaccional em água. Tratou-se a fase orgânica com sulfito de sódio e recristalizou-se em tolueno/benzeno. Obtiveram-se 247 g.A solution of 360 g (2.4 moles) of piperonal in 684 g (7.7 mole) of 2-nitropropane was added to 2.4 moles of sodium methoxide in 360 ml of freshly prepared methanol at 15 ° C. ° C. After stirring at room temperature overnight, 480 ml of 5N sulfuric acid was added. Then, the reaction mixture was poured into water. The organic phase was treated with sodium sulfite and recrystallized from toluene / benzene. 247 g were obtained.
A uma solução de 247 g em benzeno adicionou-se 141 g de cloreto de tionilo em 250 ml de benzeno. Após refluxo durante 4 horas evaporou-se o dissolvente e o excesso de cloreto de tionilo obtendo-se um resíduo oleoso que se recristalizou em álcool isopropílico. Rendimento 140 g.To a solution of 247 g in benzene was added 141 g of thionyl chloride in 250 ml of benzene. After reflux for 4 hours, the solvent and excess thionyl chloride were evaporated to obtain an oily residue which was recrystallized from isopropyl alcohol. Yield 140 g.
Dissolveu-se em 200 ml de dioxano 26 g deste composto (0,1 mole). Adicionou-se 0,3 g de Pd/BaSO^ seguido da hidrogenação a 1 atmosfera e à temperatura ambiente. A filtração e a26 g of this compound (0.1 mole) was dissolved in 200 ml of dioxane. 0.3 g of Pd / BaSO4 was added followed by hydrogenation in 1 atmosphere and at room temperature. Filtration and
evaporação deram um resíduo oleoso que se dissolveu em 150 ml de etanol adicionando-se 1 g de paládio sobre carvão a 10Z. A 2 hidrogenaçao processou-se a 3,5 kg/cm (50 psi) durante a noite e obteve-se o produto após filtração e evaporação. A recristalização deu 11,5 g do produto.evaporation gave an oily residue which dissolved in 150 ml of ethanol by adding 1 g of palladium on charcoal at 10Z. Hydrogenation was carried out at 3.5 kg / cm (50 psi) overnight and the product was obtained after filtration and evaporation. Recrystallization gave 11.5 g of the product.
RMN: (cloridrato em CDCl^, referência TMS) d; 8,45 (-NH^); 6,8-6,6 (aromático); 5,9 (OCl^O); 2,9 (-CH2-); 1,4 (-CH3).NMR: (hydrochloride in CDCl3, reference TMS) d; 8.45 (-NH ^); 6.8-6.6 (aromatic); 5.9 (OCl ^ O); 2.9 (-CH 2 -) ; 1.4 (-CH 3 ).
Composto S6 l-(3,4-dimetoxifenil)-2-(R/S)-aminopropanoCompound S6 1- (3,4-dimethoxyphenyl) -2- (R / S) -aminopropane
Dissolveram-se 20 g (0,12 mole) de 3,4-dimetoxibenzaldeído em 100 ml de nitrometano. Adicionaram-se 3 ml de butilamino.20 g (0.12 mole) of 3,4-dimethoxybenzaldehyde was dissolved in 100 ml of nitromethane. 3 ml of butylamino was added.
Após refluxo num aparelho de Dean-Stark durante 2 horas, seguida de evaporaçao, obteve-se um óleo castanho. A recristalização em álcool isopropílico deu 16,6 g.After reflux in a Dean-Stark apparatus for 2 hours, followed by evaporation, a brown oil was obtained. Recrystallization from isopropyl alcohol gave 16.6 g.
Adicionaram-se, gota a gota, 16,4 g (0,07 mole) de nitroestireno a 8 g de hidreto de alumínio e lítio em 1 litro de éter dietílico anidro. Continuou-se a agitar durante a noite. Após transformaçao obteve-se um óleo amarelado. Preparou-se o sulfato a partir de uma solução de éter dietílico/etanol obtendo-se 10,4 g (sulfato).16.4 g (0.07 mole) of nitrostyrene was added dropwise to 8 g of aluminum and lithium hydride in 1 liter of anhydrous diethyl ether. Stirring continued overnight. After transformation, a yellowish oil was obtained. The sulfate was prepared from a diethyl ether / ethanol solution to obtain 10.4 g (sulfate).
-31Composto S4-31Composition S4
1-(3,4-metilenodioxifenil)-2-(R/S)-aminopropano1- (3,4-methylenedioxyphenyl) -2- (R / S) -aminopropane
Preparou-se de acordo com Beng T Wo et al, J.Med. Chem. 13 (1970) 26.It was prepared according to Beng T Wo et al, J. Med. Chem. 13 (1970) 26.
Composto S7Compound S7
Preparou-se analogamente l-fenil-2-(R/S)-aminopropano.1-Phenyl-2- (R / S) -aminopropane was similarly prepared.
-33Em seguida descreve-se a preparaçao dos compostos apresentados no Quadro 3:-33 Next, the preparation of the compounds shown in Table 3 is described:
Procedimento geral· para a preparação dos compostos de fórmula geral· VII na qual representa um átomo de hidrogénioGeneral procedure · for the preparation of compounds of general formula · VII in which it represents a hydrogen atom
Submeteu-se a refluxo o óxido de 4-benziloxi-3-nitroestireno com uma amina apropriada em metanol durante uma noite ou mais tempo. Purifiçaram-se os produtos por cromatografia em gel de sílica utilizando clorofórmio como eluente.The 4-benzyloxy-3-nitrostyrene oxide was refluxed with an appropriate amine in methanol for one night or longer. The products were purified by chromatography on silica gel using chloroform as the eluent.
1-(4-benziloxi-3-nitrofenil)-2-(l-metil-2-(3,4-metilenodioxifenil) -etilamino) -etanol (racemato R,S + S,R e racemato R,R + S,S)1- (4-benzyloxy-3-nitrophenyl) -2- (1-methyl-2- (3,4-methylenedioxyphenyl) -ethylamino) -ethanol (R, S + S, R and R, R + S racemate, S)
Descrito no Exemplo 2 citado anteriormente.Described in Example 2 mentioned above.
Composto 1919
1-(4-benziloxi-3-nitrofenil·)-2 - (l-metil-2-(3,4-dimetoxifenil)-etilamino)-etanol (mistura isomérica de R,R R,S S,S e S,R).1- (4-benzyloxy-3-nitrophenyl ·) -2 - (1-methyl-2- (3,4-dimethoxyphenyl) -ethylamino) -ethanol (isomeric mixture of R, RR, SS, S and S, R) .
A partir de 4,3 g da amina e 5,4 g do epóxido obtiveram-seFrom 4.3 g of the amine and 5.4 g of the epoxide,
5,2 g do produto sob a forma de um óleo.5.2 g of the product as an oil.
-34Procedimento geral para a preparaçao de compostos de fórmula geral VII na qual representa um grupo CmCH^Ph-34General procedure for the preparation of compounds of general formula VII in which it represents a CmCH ^ Ph group
Submeteu-se a aquecimento uma amina VI sob uma corrente de azoto seco, com óxido de 4-benziloxi-3-nitroestireno ã temperatura de 150°C durante a noite. Purificou-se o produto por cromatograf ia em gel de sílica utilizando clorofórmio como eluente.An amine VI was subjected to heating under a stream of dry nitrogen, with 4-benzyloxy-3-nitrostyrene oxide at 150 ° C overnight. The product was purified by chromatography on silica gel using chloroform as the eluent.
Composto 15Compound 15
1-(4-benziloxi-3-nitrofenil)-2-(N-metilbenzil-N-(1-metoxifenil)-2-propilamino)-etanol (mistura isomérica R,S,S + + S,S,S)1- (4-benzyloxy-3-nitrophenyl) -2- (N-methylbenzyl-N- (1-methoxyphenyl) -2-propylamino) -ethanol (isomeric mixture R, S, S + + S, S, S)
A partir de 5,1 g de uma amina de fórmula geral VI e deFrom 5.1 g of an amine of general formula VI and
5,4 g de epóxido obtiveram-se 7,7 g de um óleo.5.4 g of epoxide, 7.7 g of an oil were obtained.
RMN: (CDCl^ e TMS como referência) d; 7,86-6,71 (m, 12H); 5,25 (s, 1H); 5,23 (s, 1H); 4,58 (m, 1/2 H); 4,37 (m, 1/2 H); 4,10 (m, 2H); 3,77 (s, 1,5H); 3,75 (s, 1,5H); 3,78 (m, 1/2 H) ; 3,25-2,40 (m, ); 2,15 (m ); 16 (dd, 3H); 1,0 (dd, 3H).NMR: (CDCl ^ and TMS as reference) d; 7.86-6.71 (m, 12H); 5.25 (s, 1H); 5.23 (s, 1H); 4.58 (m, 1/2 H); 4.37 (m, 1/2 H); 4.10 (m, 2H); 3.77 (s, 1.5H); 3.75 (s, 1.5H); 3.78 (m, 1/2 H); 3.25-2.40 (m,); 2.15 (m); 16 (dd, 3H); 1.0 (dd, 3H).
Composto 1616
1-(4-benziloxi-3-nitrofenil)-2-(N-l-fenil-2-propilamino)-etanol1- (4-benzyloxy-3-nitrophenyl) -2- (N-1-phenyl-2-propylamino) -ethanol
-35A partir de 4,8 g de uma amina de fórmula geral VI e de-35From 4.8 g of an amine of general formula VI and from
5,4 g de epóxido obtiveram-se 2,5 g de produto oleoso.5.4 g of epoxide 2.5 g of oily product were obtained.
Composto 110110
1-(4-benziloxi-3-nitrofenil)-2-(1,l-dimetil-l-(3,4-metileno dioxifenil)-etilamino)-etanol (racemato)1- (4-benzyloxy-3-nitrophenyl) -2- (1,1-dimethyl-1- (3,4-methylene dioxiphenyl) -ethylamino) -ethanol (racemate)
Apartir de 4,8 g de uma amina de fórmula geral VI e deStarting from 4.8 g of an amine of general formula VI and
5,4 g de epóxido obtiveram-se 7,4 g do produto.5.4 g of epoxide 7.4 g of the product were obtained.
RMN: (CDC13 e TMS como referência) d; 7,85 (d, IH); 7,52-6,52 (m, H); 5,91 (s, 2H); 5,22 (s, 2H);NMR: (CDC1 3 and TMS as a reference) d; 7.85 (d, IH); 7.52-6.52 (m, H); 5.91 (s, 2H); 5.22 (s, 2H);
4.56 (dd, IH); 2,91 (dd, IH); 2,58 (s, 2H);4.56 (dd, IH); 2.91 (dd, IH); 2.58 (s, 2H);
2.56 (m, IH); 1,04 (2s, 6H).2.56 (m, IH); 1.04 (2s, 6H).
Compostos II, 12, 13 e 14Compounds II, 12, 13 and 14
1-(4-benziloxi-3-nitrofenil)-2-(l-metil-2-(3,4-metilenodioxifenil)-etilamino)-etanol·1- (4-benzyloxy-3-nitrophenyl) -2- (1-methyl-2- (3,4-methylenedioxyphenyl) -ethylamino) -ethanol ·
A preparação dos isómeros R,R,R, R,S,S, S,S,S e S,R,R foi descrita anteriormente no Exemplo 1.The preparation of the R, R, R, R, R, S, S, S, S, S and S, R, R isomers was described previously in Example 1.
Também a preparaçao dos compostos que seguem no Quadro 4 foi descrita anteriormente no Exemplo 1.Also the preparation of the compounds that follow in Table 4 was described previously in Example 1.
-36Quadro 4-36Picture 4
Compostos intermédios de fórmula geral VIIIIntermediate compounds of general formula VIII
VIIIVIII
Composto R2 R3 R4Compound R 2 R 3 R 4
EstereoqulmicaStereochemistry
Os exemplos que compostos da presente çoes farmacêuticas:Examples that comprise of the present pharmaceutical stocks:
se seguem exemplificam a forma como os invenção se podem incorporar em composi-37-The following illustrate how the inventions can be incorporated into compositions.
Exemplo PI. Aerossol para inalaçaoExample PI. Aerosol for inhalation
Composto de acordo com o Exemplo 1 ou 2 Trioleato de sorbitanoCompound according to Example 1 or 2 Sorbitan trioleate
Frigen 11/12/114 atéFrigen 12/11/114 until
Exemplo P2. ComprimidosExample P2. Pills
Cada comprimido contém:Each tablet contains:
Compostos de acordo com o Exemplo 1Compounds according to Example 1
Amido de milhoMaize starch
LactoseLactose
PovidonaPovidona
Celulose microcristalinaMicrocrystalline cellulose
Estearato de magnésioMagnesium stearate
Exemplo P3. SupositóriosExample P3. Suppositories
Cada supositório contém:Each suppository contains:
Composto de acordo com o Exemplo 1Compound according to Example 1
Palmitato de ascorbiloAscorbyl palmitate
Base para supositórios (Imhausen H) atéSuppository base (Imhausen H) up to
0,75 g 0,20 g0.75 g 0.20 g
100,0 g100.0 g
6,0 mg 78,0 mg 125,0 mg6.0 mg 78.0 mg 125.0 mg
7,0 mg 13,0 mg7.0 mg 13.0 mg
1,6 mg1.6 mg
6,0 mg 1,0 mg6.0 mg 1.0 mg
000,0 mg000.0 mg
-38Exemplo P4. Xarope-38Example P4. Syrup
Compostos de acordo com o Exemplo 1Compounds according to Example 1
Glucose líquidaLiquid glucose
SacaroseSucrose
Ácido ascórbicoAscorbic acid
Pirossulfito de sódioSodium pyrosulfite
Edetato de dissódioDisodium edetate
Essência de laranjaOrange essence
Cor certificadaCertified color
Água purificadaPurified water
Exemplo P5. Solução para inalaçãoExample P5. Inhalation solution
Composto de acordo com o Exemplo 1 Pirossulfito de sódioCompound according to Example 1 Sodium pyrosulfite
Edetato de dissódioDisodium edetate
Cloreto de sódioSodium chloride
Água purificadaPurified water
0,060 g 30,0 g 50,0 g0.060 g 30.0 g 50.0 g
0,1 g0.1 g
0,01 g0.01 g
0,01 g0.01 g
0,025 g0.025 g
0,015 g até 100,0 ml0.015 g to 100.0 ml
0,75 g 0,10 g 0,10 g 0,85 g até 100,0 ml0.75 g 0.10 g 0.10 g 0.85 g up to 100.0 ml
Exemplo P6. Solução para administração rectal (Ampolas rectais)Example P6. Solution for rectal administration (rectal ampoules)
Exemplo P9Example P9
Um composto de acordo com o Exemplo 1 com estereoquímica R,S micronizou-se para se obterem partículas de dimensão apropriada para a terapêutica inalatória. Acondicionou-se a subsΛ D tancia em po no inalador Turbuhaler .A compound according to Example 1 with R, S stereochemistry was micronized to obtain particles of appropriate size for inhalation therapy. Acondicionou to Λ D subs sub- stance in Turbuhaler powder inhaler.
-40t ' 7'-40t '7'
A dose habitual diária da substância activa varia grandemente, dependendo de vários factores como, por exemplo, exigências individuais do doente, a via de administração e a doença.The usual daily dose of the active substance varies widely, depending on several factors, such as individual patient requirements, the route of administration and the disease.
De um modo geral, as doses orais e parentéricas devem estar compreendidas entre 0,5 e 15 mg por dia de substância activa. A substância activa também se pode incluir sob a forma de composições farmacêuticas contendo uma associaçao do composto activo com brometo de Ipratrópio ou Budesonido.In general, oral and parenteral doses should be between 0.5 and 15 mg per day of active substance. The active substance can also be included in the form of pharmaceutical compositions containing an association of the active compound with Ipratropium bromide or Budesonide.
Avaliação farmacológicaPharmacological evaluation
1. Estudo na cobaia, in vivo, da duração da acção broncodilatadora1. Study in guinea pig, in vivo, of the duration of bronchodilator action
A. MétodoA. Method
Neste estudo utilizaram-se cobaias em vigília. Os compostos de acordo com os Exemplos 1 e 2, salmeterol e terbutalina, foram administrados por via inalatória ou por instilação na traqueia depois do que os animais foram provocados com uma névoa de hista mina após diferentes intervalos de tempo.In this study, guinea pigs were used during vigil. The compounds according to Examples 1 and 2, salmeterol and terbutaline, were administered by inhalation or by instillation in the trachea after which the animals were challenged with a mine mist after different time intervals.
a. InalaçãoThe. Inhalation
Colocaram-se as cobaias em caixas de plástico e libertaram-se os compostos em ensaio mediante uma nebulisação contínua durante 15 minutos.Guinea pigs were placed in plastic boxes and the test compounds were released by continuous nebulisation for 15 minutes.
-41b. Instilação traqueal-41b. Tracheal instillation
Anestesiaram-se ligeiramente os animais por inalação de efrano. Instilaram-se os compostos em ensaio através de uma cânula fina na bifurcação da traqueia. Nos animais que constituíam o controlo instilou-se solução de cloreto de sódio.The animals were anesthetized slightly by inhaling efrane. The test compounds were instilled through a fine cannula at the bifurcation of the trachea. In the animals that constituted the control, sodium chloride solution was instilled.
c. Processo de provocaçãoç. Provocation process
Após a administração, de acordo com uma das vias mencionadas anteriormente, colocaram-se os animais em gaiolas de plástico transparente e provocaram-se com histamina em aerossol.After administration, according to one of the routes mentioned above, the animals were placed in transparent plastic cages and challenged with aerosolized histamine.
nevoeiro de aerossol foi gerado no nebulisador a partir de uma -3 solução que continha 0,5-1,0 x 10 mole/1 de histamina em glicerol a 3Z. Esta concentração produziu o aparecimento de uma respiração dispnótica definida nos animais de controlo em 2 ou 3 minutos. Esta fase foi habitualmente indicada por observação, algumas vezes também através de um ensaio cego ou foi registada mediante a aplicação de uma cinta escalonada (strain-gauge belt) (ver O.A.T. Olsson in Acta Allergologic 26 (1971) 438).aerosol fog was generated in the nebulizer from a -3 solution that contained 0.5-1.0 x 10 mole / 1 histamine in 3Z glycerol. This concentration produced the appearance of a dyspnotic breath defined in the control animals in 2 or 3 minutes. This phase was usually indicated by observation, sometimes also through a blind test, or was recorded by applying a step-belt (strain-gauge belt) (see O.A.T. Olsson in Acta Allergologic 26 (1971) 438).
Uma quantidade crescente do agente espasmolítico administrada em seguida permite o prolongamento, dependente da dose, da capacidade dos animais para resistirem a este espasmo histamínico.An increasing amount of the spasmolytic agent administered thereafter allows the dose-dependent extension of the animals' ability to resist this histamine spasm.
Logo que a respiração dispnótica se apresentou, retiraram-se as cobaias do meio com histamina, visto que os mesmos animais deveriam ser expostos à histamina não só após 30 minutos mas também 3,6 e 9 horas depois da administração do fãrmaco.As soon as dyspnotic respiration started, the guinea pigs were removed from the medium with histamine, since the same animals should be exposed to histamine not only after 30 minutes but also 3.6 and 9 hours after the drug was administered.
Em algumas das experiências os animais foram provocados com metacolina em substituição da histamina, para excluir qualquer efeito eventual antihistamínico do fármaco ensaiado.In some of the experiments, the animals were challenged with methacholine in place of histamine, to exclude any possible antihistamine effect of the drug being tested.
B. ResultadosB. Results
Os agonistas dos receptores-β salmeterol e terbutalina foram ambos utilizados na terapêutica inalatória e escolhidos como compostos de referência neste estudo em que o novo agonista-β , de acordo com a presente invenção, se avaliou no que se refere à duraçao da acçao das actividades broncodilatadoras.The β-receptor agonists salmeterol and terbutaline were both used in inhalation therapy and were chosen as reference compounds in this study in which the new β-agonist, in accordance with the present invention, was evaluated with regard to the duration of action of activities bronchodilators.
De um modo geral, as potências iniciais dos novos compostos de acordo com os Exemplos 1 e 2 são aproximadamente as mesmas que a da terbutalina mas cerca de 10 vezes menores do que as do salmeterol. A duração da acção, calculada a partir de uma taxa equipotente é, contudo, prolongada, nos novos compostos da presente invenção e com o salmeterol quando se compara com a terbutalina. Em comparação com o salmeterol, a duração do efeito dos novos compostos, parece ainda ser algo mais prolongada.In general, the starting potencies of the new compounds according to Examples 1 and 2 are approximately the same as that of terbutaline but about 10 times less than that of salmeterol. The duration of action, calculated from an equipotent rate, however, is prolonged, in the new compounds of the present invention and with salmeterol when compared to terbutaline. Compared to salmeterol, the duration of effect of the new compounds appears to be somewhat longer.
Os compostos apresentados no Quadro 5 são 1-(4-hidroxi)-3-(£-metoxibenzilamino)-fenil-2-(l-metil-2-(3,4-metilenodioxifenil ) -etil ) -amino ) -etanóis quer sob a forma de uma mistura racémica quer sob a forma de um dos seus isómeros.The compounds shown in Table 5 are 1- (4-hydroxy) -3- (£ -methoxybenzylamino) -phenyl-2- (1-methyl-2- (3,4-methylenedioxyphenyl) -ethyl) -amino) -ethanols in the form of a racemic mixture or in the form of one of its isomers.
Quadro 5Table 5
Solução salina (controlo)Saline solution (control)
Z2 2Z2 2
As quantidades instiladas, produzem, aproximadamente, uma protecção igualmente eficaz (6 a 7 minutos) contra provocação histamínica 30 minutos após a administração do composto de ensaio. O grau de protecção , 6 horas após a instilação do composto do ensaio, indica a duraçao da actividade broncospasmolítica.The amounts instilled produce approximately equally effective protection (6 to 7 minutes) against histamine challenge 30 minutes after administration of the test compound. The degree of protection, 6 hours after instillation of the test compound, indicates the duration of bronchospasmolytic activity.
-Μ--Μ-
II. Estudo do efeito broncospasmolitico e da estimulação cardíaca em cobaias anestesiadasII. Study of bronchospasmolytic effect and cardiac stimulation in anesthetized guinea pigs
A finalidade deste estudo foi comparar os agonistas ^5-receptores de acordo com a presente invenção com o salmeterol e a terbutalina na capacidade para inibirem o espasmo respiratório nas cobaias anestesiadas, após injecçao endovenosa ou após inalação. Além disso, avaliou-se a influência dos compostos testados na frequência cardíaca.The purpose of this study was to compare the 5-receptor agonists according to the present invention with salmeterol and terbutaline in the ability to inhibit respiratory spasm in anesthetized guinea pigs, after intravenous injection or after inhalation. In addition, the influence of the tested compounds on heart rate was evaluated.
MétodosMethods
a. Administração endovenosaThe. Intravenous administration
Utilizaram-se neste estudo cobaias de ambos os sexos.Guinea pigs of both sexes were used in this study.
Obteve-se a anestesia com pentobarbital endovenoso. Instilou-se uma cânula traqueal e ventilaram-se os animais artificialmente com um volume respiratório constante. A pressão intratraqueal (ITP) foi avaliada por um transdutor de pressão. 0 aumento na ITP acima da taxa de pressão básica, que indica um espasmo respiratório, foi provocado pela histamina perfundida na veia jugular durante 20 segundos de 7 em 7 minutos e em quantidades que produziam uma pressão intratraqueal máxima compreendida entre 4 e 6 kPa. Para seguir os efeitos cardiovasculares dos fármacos utilizados, registou-se a tensão arterial na artéria carótida por meio de um transdutor de pressão. A pulsação, que indica a frequência, foi registada por um tacógrafo que indica a frequência cardíaca.Anesthesia with intravenous pentobarbital was obtained. A tracheal cannula was instilled and the animals were artificially ventilated with a constant respiratory volume. Intratracheal pressure (ITP) was assessed by a pressure transducer. The increase in ITP above the basic pressure rate, which indicates a respiratory spasm, was caused by histamine perfused in the jugular vein for 20 seconds every 7 minutes and in quantities that produced a maximum intratracheal pressure between 4 and 6 kPa. To follow the cardiovascular effects of the drugs used, blood pressure was recorded in the carotid artery using a pressure transducer. The pulse, which indicates the frequency, was recorded by a tachograph that indicates the heart rate.
-45Os compostos de ensaio injectaram-se 3 minutos antes da perfusão de histamina e considerou-se a diminuição em percentagem da pressão intratraqueal (ITP) como a medida da actividade broncospasmolítica. A influência sobre a frequência cardíaca foi avaliada após injecções cumulativas; deu-se uma nova injecção quando a antecedente produziu um estado estacionário na frequência.The test compounds were injected 3 minutes prior to the histamine infusion and the percentage decrease in intratracheal pressure (ITP) was considered to be a measure of bronchospasmolytic activity. The influence on heart rate was assessed after cumulative injections; a new injection was given when the antecedent produced a steady state in the frequency.
b. Administração por inalaçaoB. Administration by inhalation
Os compostos de ensaio nebulisaram-se produzindo uma neblina que foi introduzida no animal através de uma cânula respiradora traqueal. Continuou-se a inalaçao durante 15 minutos para cada concentração do composto em ensaio. 0 efeito broncodilatador sobre a frequência cardíaca calculou-se como a frequência redução e percentagem da pressão intratraqueal (ITP). 0 efeito sobre a cardíaca determinou-se após um aumento cumulativo das concentrações das soluçoes nebulisadas. As avaliações do efeito foram consideradas no estado estacionário utilizando três concentrações diferentes.The test compounds were nebulized, producing a fog that was introduced into the animal through a tracheal respiratory cannula. Inhalation was continued for 15 minutes for each concentration of the test compound. The bronchodilator effect on heart rate was calculated as the rate of reduction and percentage of intratracheal pressure (ITP). The effect on the cardiac was determined after a cumulative increase in the concentrations of the nebulized solutions. Effect assessments were considered at steady state using three different concentrations.
B. Resultados a. Efeitos respiratóriosB. Results a. Respiratory effects
Os três agonistas dos receptores-β utilizados, os compostos de acordo com o Exemplo 2, salmeterol e terbutalina, demonstraramThe three β-receptor agonists used, the compounds according to Example 2, salmeterol and terbutaline, demonstrated
todos uma inibição dependente da dose de broncospasmo provocado peia histamina após injecção ou após inalação. 0 salmeterol foi o composto mais activo e com uma potência pelo menos 10 vezes superior ã dos outros dois fármacos quando injectado e cerca de 5 vezes quando inalado. A injecção de 5x10 . mole/kg de salmeterol, 5x10 mole/kg do composto de acordo com o Exemplo 2 ou q 1x10 mole/kg de terbutalina forneceu cerca de uma redução de 50Z na pressão intratraqueal.all a dose-dependent inhibition of bronchospasm caused by histamine after injection or after inhalation. Salmeterol was the most active compound and had a potency at least 10 times that of the other two drugs when injected and about 5 times when inhaled. The 5x10 injection. mole / kg of salmeterol, 5x10 mole / kg of the compound according to Example 2 or q 1x10 mole / kg of terbutaline provided about a 50Z reduction in intratracheal pressure.
b. Efeito na frequência cardíaca efeito na frequência cardíaca foi dependente da dose e pareceu principalmente depender duma actividade directa do composto do ensaio em vez de ser um resultado de uma modificação da tensão arterial. Foi possível demonstrar uma influência depen dente da dose sobre a frequência cardíaca, não somente após injecção endovenosa mas também após inalaçao quando se injectou salmeterol ou terbutalina a frequência cardíaca foi superior à obtida com o composto da presente invenção e uma dose de 1x10 ? mole/kg de salmeterol e terbutalina aumentou a frequência cardíaca em cerca de 30 batimentos/minuto. Para alcançar o mesmo aumento na frequência cardíaca com os compostos da presente invenção, tem que se administrar uma dose pelo menos 10 vezes superior. A inalação de 5x10 mole/litro de salmeterol aumentou a frequência cardíaca em cerca de 15 batimentos/minuto. 0 mesmo aumento da frequência cardíaca foi produzido com 5x10 mole/1 pelos compostos talina se situe da presente invenção, embora o efeito da terbuentre os dois.B. Effect on heart rate effect on heart rate was dose dependent and appeared to depend mainly on direct activity of the test compound rather than a result of a change in blood pressure. Was it possible to demonstrate a dose-dependent influence on heart rate, not only after intravenous injection but also after inhalation when salmeterol or terbutaline was injected, was the heart rate higher than that obtained with the compound of the present invention and a dose of 1x10? mole / kg of salmeterol and terbutaline increased the heart rate by about 30 beats / minute. To achieve the same increase in heart rate with the compounds of the present invention, a dose of at least 10 times greater must be administered. Inhaling 5x10 mole / liter of salmeterol increased the heart rate by about 15 beats / minute. The same increase in heart rate was produced with 5x10 mole / 1 by the talina compounds is found in the present invention, although the effect of terbuent between the two.
A relação entre o efeito sobre o sistema respiratório e sobre o coraçao é a mesma para o composto de acordo com o Exemplo 2 e para o salmeterol, quando os fármacos sao injectados Contudo, esta relaçao nao parece ser a mesma quando por inalaçao Neste caso, o composto de acordo com o Exemplo 2 demonstra um efeito mais reduzido sobre a frequência cardíaca do que o salmeterol.The relationship between the effect on the respiratory system and on the heart is the same for the compound according to Example 2 and for salmeterol, when drugs are injected. However, this relationship does not appear to be the same when inhaled. In this case, the compound according to Example 2 demonstrates a lower effect on heart rate than salmeterol.
ConclusãoConclusion
Os compostos de acordo com a presente invenção têm uma duração de acção mais longa do que a terbutalina. Além disso, exibem menor efeito no coraçao do que o salmeterol.The compounds according to the present invention have a longer duration of action than terbutaline. In addition, they exhibit less effect on the heart than salmeterol.
A melhor forma de realizar a presente invenção conhecida até ao momento é utilizar o composto l-(R)-(4-hidroxi)-3-(£-metoxibenzilamino)-fenil-2-[(1-metil-1-(S)-3,4-(metilenodioxifenil)-etil)-amino]-etanol.The best way to carry out the present invention known to date is to use the compound 1- (R) - (4-hydroxy) -3- (£ -methoxybenzylamino) -phenyl-2 - [(1-methyl-1- (S ) -3,4- (methylenedioxyphenyl) -ethyl) -amino] -ethanol.
Claims (9)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8901060A SE8901060D0 (en) | 1989-03-28 | 1989-03-28 | NEW COMPOUNDS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PT93576A PT93576A (en) | 1990-11-07 |
| PT93576B true PT93576B (en) | 1996-03-29 |
Family
ID=20375454
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT93576A PT93576B (en) | 1989-03-28 | 1990-03-27 | METHOD FOR PREPARING NEW PHENYLAMINOETHANOL DERIVATIVES WITH BRONCHOSPASMOLITIC ACTIVITY AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Country Status (30)
| Country | Link |
|---|---|
| EP (1) | EP0390762B1 (en) |
| JP (1) | JPH02286650A (en) |
| KR (1) | KR900014309A (en) |
| CN (1) | CN1045968A (en) |
| AR (1) | AR247197A1 (en) |
| AT (1) | ATE100437T1 (en) |
| AU (1) | AU618171B2 (en) |
| CA (1) | CA2013114A1 (en) |
| CZ (1) | CZ280747B6 (en) |
| DD (1) | DD297805A5 (en) |
| DE (1) | DE69006071T2 (en) |
| DK (1) | DK0390762T3 (en) |
| EG (1) | EG18954A (en) |
| ES (1) | ES2062495T3 (en) |
| FI (1) | FI901528A0 (en) |
| HK (1) | HK123396A (en) |
| HR (1) | HRP920765A2 (en) |
| HU (1) | HUT58043A (en) |
| IE (1) | IE64851B1 (en) |
| IL (1) | IL93799A (en) |
| IS (1) | IS1581B (en) |
| LT (1) | LT3979B (en) |
| LV (1) | LV10708B (en) |
| NO (1) | NO172115C (en) |
| NZ (1) | NZ232765A (en) |
| PL (1) | PL163566B1 (en) |
| PT (1) | PT93576B (en) |
| SE (1) | SE8901060D0 (en) |
| YU (1) | YU47508B (en) |
| ZA (1) | ZA901716B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6040344A (en) * | 1996-11-11 | 2000-03-21 | Sepracor Inc. | Formoterol process |
| ZA994264B (en) | 1998-07-01 | 2000-01-25 | Warner Lambert Co | Stereoisomers with high affinity for adrenergic receptors. |
| US7232837B2 (en) | 1999-06-29 | 2007-06-19 | Mcneil-Ppc, Inc. | Stereoisomers with high affinity for adrenergic receptors |
| US6472563B1 (en) | 2001-11-09 | 2002-10-29 | Sepracor Inc. | Formoterol tartrate process and polymorph |
| US7169907B2 (en) * | 2002-03-01 | 2007-01-30 | Roche Diagnostics Operations, Inc. | Derivatives, immunogens, and antibodies for detecting ecstasy-class drugs |
| EP2348013A1 (en) * | 2010-01-25 | 2011-07-27 | Inke, S.A. | Process for preparation of intermediates of arformoterol |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4072720A (en) * | 1971-01-19 | 1978-02-07 | Mobil Oil Corporation | Production of alcohol |
| US3700692A (en) * | 1971-06-04 | 1972-10-24 | Colgate Palmolive Co | 1-(4{40 -hydroxy-3{40 -(hydroxy methyl)-phenyl)-1-hydroxy-2-aralkylaminoethanes |
| GB1531718A (en) * | 1974-11-20 | 1978-11-08 | Pharmacia As | Phenylethanolamines |
-
1989
- 1989-03-28 SE SE8901060A patent/SE8901060D0/en unknown
-
1990
- 1990-03-01 NO NO900982A patent/NO172115C/en unknown
- 1990-03-02 AU AU50675/90A patent/AU618171B2/en not_active Ceased
- 1990-03-02 NZ NZ232765A patent/NZ232765A/en unknown
- 1990-03-06 ZA ZA901716A patent/ZA901716B/en unknown
- 1990-03-07 YU YU46490A patent/YU47508B/en unknown
- 1990-03-19 IL IL9379990A patent/IL93799A/en not_active IP Right Cessation
- 1990-03-23 EP EP90850112A patent/EP0390762B1/en not_active Expired - Lifetime
- 1990-03-23 DE DE69006071T patent/DE69006071T2/en not_active Expired - Fee Related
- 1990-03-23 AT AT90850112T patent/ATE100437T1/en not_active IP Right Cessation
- 1990-03-23 ES ES90850112T patent/ES2062495T3/en not_active Expired - Lifetime
- 1990-03-23 DK DK90850112.5T patent/DK0390762T3/en active
- 1990-03-26 PL PL90284473A patent/PL163566B1/en unknown
- 1990-03-27 DD DD90339108A patent/DD297805A5/en not_active IP Right Cessation
- 1990-03-27 FI FI901528A patent/FI901528A0/en not_active IP Right Cessation
- 1990-03-27 PT PT93576A patent/PT93576B/en not_active IP Right Cessation
- 1990-03-27 IE IE110490A patent/IE64851B1/en not_active IP Right Cessation
- 1990-03-27 EG EG19390A patent/EG18954A/en active
- 1990-03-27 JP JP2075790A patent/JPH02286650A/en active Pending
- 1990-03-27 CA CA002013114A patent/CA2013114A1/en not_active Abandoned
- 1990-03-27 HU HU901854A patent/HUT58043A/en unknown
- 1990-03-27 KR KR1019900004099A patent/KR900014309A/en not_active Application Discontinuation
- 1990-03-27 IS IS3567A patent/IS1581B/en unknown
- 1990-03-28 AR AR90316487A patent/AR247197A1/en active
- 1990-03-28 CZ CS901518A patent/CZ280747B6/en unknown
- 1990-03-28 CN CN90101698A patent/CN1045968A/en active Pending
-
1992
- 1992-10-01 HR HR920765A patent/HRP920765A2/en not_active Application Discontinuation
-
1993
- 1993-06-30 LV LVP-93-866A patent/LV10708B/en unknown
- 1993-12-30 LT LTIP1719A patent/LT3979B/en not_active IP Right Cessation
-
1996
- 1996-07-11 HK HK123396A patent/HK123396A/en not_active IP Right Cessation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2060992C1 (en) | Dihydroisoquinoline derivatives and a method of their synthesis | |
| KR900004143B1 (en) | Process for the preparation of quarternary 6,11-dihydro dibenzo - (b,e) - thie pine -11-n-alkyl-norscopine ethers | |
| ES2315425T3 (en) | QUATERNARY AMMONIUM COMPOUNDS AND ITS USE AS ANTIMUSCARINIC AGENTS. | |
| US5506257A (en) | Aminocyclohexylamides for antiarrhythmic and anaesthetic uses | |
| IE51373B1 (en) | New compositions of matter | |
| JPH021442A (en) | 2-(2-hydroxy-3-phenoxypropylamino) ethylphenoxyacetamide compound, its manufacture, drug containing it and used in treatment for corpulence and associated symptom, and intermediate | |
| JPS5919539B2 (en) | 3,4-dihydrocarbostyryl derivative | |
| PT94447B (en) | PROCESS FOR THE PREPARATION OF TETRAZOLIC ANTAGONISTS OF AMINO ACID RECEIVERS RECEIVERS | |
| JPS5825656B2 (en) | Dopamine energy production | |
| AU668932B2 (en) | Method of blocking sodium channels or neuronal tissue | |
| US4374149A (en) | α-{[(Arylalkyl)amino]alkyl}-4-hydroxy-3-(lower-alkylsulfinyl)benzenemethanols | |
| PT93576B (en) | METHOD FOR PREPARING NEW PHENYLAMINOETHANOL DERIVATIVES WITH BRONCHOSPASMOLITIC ACTIVITY AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
| CZ20022096A3 (en) | Quaternary ammonium compound intended for use when treating and/or prophylaxis of cough of warm-blooded animal and pharmaceutical preparation in which the compound is comprised | |
| EP2002831A1 (en) | R-Bambuterol, its preparation and therapeutic uses | |
| JPH06501252A (en) | Antiatherosclerotic aryl compounds | |
| RU2051901C1 (en) | Derivatives of 1-benzylaminophenyl-2-(1-methyl-2-phenylethylamino)-ethanol as mixture of isomers or as racemate or their pharmaceutically acceptable salts having bronchospasmolytic activity | |
| JPS638936B2 (en) | ||
| US3961072A (en) | Phenoxypropanolamine therapeutic agents | |
| FI79296B (en) | PROCEDURE FOR FRAMSTAELLNING AV 1- (2,4-DICHLOROPHENOXY) -3- (3,4-DIMETOXY- PHENETHYLAMINO) -PROPANOL- (2). | |
| US4055658A (en) | Cyanomethylphenethanolamines | |
| NZ197627A (en) | 3-and 3,5-esters of 2-(3,5-dihydroxyphenyl)ethan-2-olamine | |
| KR840001050B1 (en) | Process for the preparation of phenyl alkyl amine derivation | |
| KR820001235B1 (en) | Process for the preparation of alkylthiophenoxypropanolamines | |
| JPH0318607B2 (en) | ||
| JPH01265078A (en) | Aralkylaminoethanol heterocyclic compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG3A | Patent granted, date of granting |
Effective date: 19951221 |
|
| MM3A | Annulment or lapse |
Free format text: LAPSE DUE TO NON-PAYMENT OF FEES Effective date: 19970630 |